A systematic review of economic evaluations of pharmacological treatments for adults with chronic migraine

Background and aims Chronic migraine is a common neurovascular brain disorder with substantial economic costs. We performed a systematic review to identify economic evaluations of pharmacological treatments for adults with chronic migraine. Methods We undertook systematic literature searches using terms for migraine/headache and prophylactic drug interventions, combined with economic/cost terms where appropriate. Using inclusion and exclusion criteria, two reviewers independently assessed the citations and abstracts, and full-text articles were retrieved. A review of study characteristics and methodological quality was assessed. Results Sixteen citations met the inclusion criteria and were model-based cost-utility studies evaluating: Botox (n = 6); Erenumab (n = 8); Fremanezumab (n = 2); and Galcanezumab (n = 1) as the main treatment. They varied in their use of comparators, perspective, and model type. Botox was cost-effective compared to placebo with an incremental cost-effectiveness ratio (ICER) ranging between £15,028 (€17,720) and £16,598 (€19,572). Erenumab, Fremanezumab and Galcanezumab when compared to Botox, was associated with ICERs ranging between £59,712 ($81,080) and £182,128 (€218,870), with the ICERs above the most common willingness-to-pay thresholds (WTPs). But they were cost-effective within the commonly used WTPs among the population for whom the previous treatments including Botox were failed. Three studies compared the cost-effectiveness of Erenumab against the placebo and found that Erenumab was dominant. All studies performed sensitivity analyses to check the robustness of their results. None of the findings from the included articles were generalisable and none of the included studies fulfilled all the criteria mentioned in the CHEERS 2022 reporting checklist and Phillips’s checklist for economic models. Conclusions Evidence to support the cost-effectiveness of pharmacological treatments of chronic migraine in the adult population using Botox and Erenumab were identified. Our findings suggest that both Botox and Erenumab, are cost-effective compared to placebo; although Erenumab had more incremental economic benefits compared to Botox, the ICERs were above the most common willingness-to-pay thresholds. Hence, Erenumab might be an acceptable treatment for chronic migraine for patients whom other treatments such as Botox do not work. Further research is needed to help characterise the data to adequately structure and parameterise an economic model to support decision-making for chronic migraine therapies. Supplementary Information The online version contains supplementary material available at 10.1186/s10194-022-01492-y.


Introduction
Migraine is the world's second most common disabling disorder [1] and the top cause of years lived with disability in those aged 15-49 years [2]. Chronic migraine is a debilitating neurological condition. It is one of the most important non-transmissible disorders. The overall global prevalence of chronic migraine is between 1.4 -2.2% [1]. Migraine has huge social and economic impact on the society. For example, in the United Kingdom (UK), one out of each six adults are affected by migraine. Most commonly these are young adults with work and family commitments [3], and the economic burden in the UK is over £1.5 billion per year [3]. The definition of chronic migraine has developed over time. Version three (2018) of the international classification of headache disorder defines chronic migraine as 'Headache occurring on 15 or more days/month for more than three months, which, on at least eight days/month, has the features of migraine headache' [4]. For those affected and for the healthcare system(s), chronic migraine is a financially burdensome condition [5][6][7], this includes both direct costs such as hospitalisation and medications, and indirect costs resulting from work presenteeism and absenteeism. Prophylactic drug treatments are a core part of the management of chronic migraine [2].
The health technology assessment organisations and other decision-making bodies may use the evidence on economic evaluations to learn the economic value of the available treatments. Such kind of review should comprehensively capture the information about the cost and benefits associated with those treatments. Our literature search identified two such reviews about migraine treatment. In the first one, Yu et al. (2009) in a review of economic evaluations of drug treatments for migraine, identified three cost-effectiveness studies of drugs for migraine prophylaxis [8]. All three were studies of the episodic migraine [9][10][11]. More recently (2020), a second review about the cost-effectiveness of the treatment for migraine including chronic and episodic migraines was published, but the inclusion criteria were limited to articles published from the UK and the Ireland [12]. With the advent of newer drugs, such as calcitonin generelated peptide monoclonal antibodies (CGRP MAbs), and increased use of botulinum toxin type A (BTA) or OnabotulinumtoxinA or Botox, all of which are principally targeted at people with chronic migraine there is a need for an updated review to identify what is known about the cost-effectiveness of prophylactic drugs when used for chronic migraine at a global level. Hence, we have conducted a systematic review to identify all economic evaluations of prophylactic drug treatments for the treatment of chronic migraine, regardless of study design (trial-based economic evaluation or model-based economic evaluation).

Search strategy
Working with an information specialist (AB), we developed a search initially constructed in MEDLINE, using both free text keywords and thesaurus (MeSH) terms for migraine/headache and prophylactic drug interventions (including named drugs of interest). These were combined with a search filter for economic and cost studies. No language nor date limits were applied. Search strategies in economics/HTA specific sources included only terms for migraine/headache, with the addition of general terms for drug treatment or prevention in some cases. An example of the MEDLINE search strategy can be found in Additional file 1: Appendix 1. This search strategy was checked by another information specialist, not otherwise involved in the project, for errors in spelling, search syntax or structure prior to being run in MEDLINE and translated to other databases. The following bibliographic databases were searched on 6th September 2021.
• MEDLINE All, 1946 23:122 Consortium (SMC), All Wales Medicine Strategy Group (AWMSG) and Canadian Agency for Drugs and Technology in Health (CADTH) were also searched on 7th September 2021 for publications relating to migraine or headache. We summarised the published journal articles separately from the reports, as the latter will not have had a formal peer-reviewed process. We used End-Note X20 to manage references including the removal of duplicates.
The review and updates were performed in accordance with the methodological principles of conduct for systematic reviews as reported in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [13]. No ethical approval was required. The protocol is registered with the international prospective register of systematic reviews (PROSPERO) database (reference number: CRD42021265995).
We included full economic evaluations in which both the costs and the outcomes of interventions and alternatives are examined including both trial-based and modelbased evaluations. We included four types of economic evaluations: cost-benefit analysis [CBA], cost-consequence analysis [CCA], cost-effectiveness analysis [CEA], and cost-utility analysis [CUA]. We excluded partial economic evaluations, systematic reviews, meta-analyses, qualitative studies, conference abstracts, editorials, short commentary and study protocols.

Population
Adults with chronic migraine, where the headache occurred for 15 or more days/month for more than 3 months.

Comparators
Placebo, usual care, or other prophylactic drugs. Any articles comparing pharmacotherapy with non-pharmacological interventions were excluded.

Outcomes
Measures included but not limited to: headache/migraine days, headache-related quality of life including Headache Impact Test 6 (HIT-6), Migraine Disability Assessment Score (MIDAS), and migraine specific quality of life, acute treatment use, headache intensity and duration, health service activity, days lost from usual activities, incremental cost-effectiveness ratios (ICER) (e.g., cost per disability-adjusted life year [DALY] averted, cost per quality-adjusted life year [QALY] gained).

Study selection procedure
The citations including title and abstracts were first assessed against the eligibility criteria by two independent reviewers (HM and SK). Where the applicability of the inclusion criteria was unclear, the article was included in the next stage to ensure that all potentially relevant studies were identified. Full-text copies of publications potentially meeting the eligibility criteria were then obtained and reviewed against the same eligibility criteria by two reviewers (HM and SK). At both the title/ abstract and full-text review stages, any disagreements between the reviewers were resolved by discussion until a consensus was met, with a third independent reviewer making the final decision if necessary (MU). No language restrictions were applied.

Data extraction
For full-text studies, data were extracted by a single reviewer (SK) into a pre-specified data extraction form and was independently checked for completeness and accuracy by a second reviewer (SN).
Extracted information included the following: • Details of study context (authors, publication year, country, setting, study population, intervention and comparators). • A detailed account of the economic evaluation methods and results (type of economic evaluation, model type, study perspective, time horizon, currency and price year, discount rate, resource use/costs, outcome measures, analytical methods, results, sensitivity analyses, generalisability, conclusion, source of funding and conflicts of interest).

Quality appraisal of economic evaluations
To allow a comparison of the economic evaluation methods used in the studies, the reporting quality of both the trial-based and model-based economic evaluations were assessed using the CHEERS 2022 checklist [14] which is a commonly used generic quality assessment tool of reporting standards. The quality of each model-based economic evaluation was further assessed using the Philips checklist [15]. The quality assessment checklists provide a systematic and critical descriptive overview of key methodological elements. Quality assessment was undertaken by one reviewer (SK) and was independently checked for completeness and accuracy by a second reviewer (SN).

Results
After deduplication, we identified 2927 citations from the database searches and reviewed them at the title/ abstract review stage. After title/abstract review, 75 articles were reviewed in the full-text stage and nine articles [16][17][18][19][20][21][22][23][24] ultimately met the inclusion criteria for published peer-reviewed journal articles. One article was translated from Bulgarian [24] and one article was translated from Italian [22]. Our translation is available on request from the corresponding author. We also found an additional 51 reports and after the screening, we were left with seven reports [25][26][27][28][29][30][31] which were identified through other methods, such as Google, Google Scholar and websites of NICE, SMC, AWMSG and CADTH that were not published in peer review journals. The flow of studies through the systematic review process is presented in Fig. 1. We have narratively synthesised the reporting of the nine published journal articles separately from the seven reports.

Context, types of economic evaluation, interventions and comparators
Among the nine included studies from the database search, the majority of studies (n = 7) [17-21, 23, 24] were published during the last 5 years. All studies originated from high-income countries, mainly countries in European Union (n = 5) [17,18,21,22,24], including two each in the UK [16,19] and the United States [20,23]. All the evaluations were model-based cost-utility analyses involving hypothetical cohorts of the participants with chronic migraine [16][17][18][19][20][21]23]. Among the nine included studies, four studies [16,18,19,22] evaluated Botox and five studies [17,20,21,23,24] evaluated Erenumab for the treatment of chronic migraine. All the studies evaluating Botox [16,18,19,22] compared the treatment with placebo or the best supportive care. As no established standard of care existed participants took their usual acute headache medications, placebo treatment (injection of saline water) was also considered as a comparator and assumed to represent consultant appointments to tailor acute medication, such as triptans. Those studies evaluating Erenumab compared the outcomes with Botox as a primary comparator or as a part of a sensitivity analysis. Further details about the interventions and comparators are presented in Table 1.

Modelling approach, perspective and time horizon used in the models
All of the journal articles were cost-utility studies. The majority (n = 6) [16, 18-20, 22, 24] of studies utilised a Markov state-transition model structure. Markov models commonly included health states stratified by the number of migraine or headache days per 28 days and allowed for treatment discontinuation or treatment on/ off periods. One study used a decision tree, and the other two studies were based on the hybrid models: the first, a hybrid of decision tree and Markov model and the second, a hybrid of a Monte Carlo simulation and Markov model. The time horizon most utilised was two-years, however, the length varied from 1 year to 10 years. The studies from the United Kingdom were conducted from the National Health Service (NHS) perspective, the European studies were based on the societal perspective and the American studies were based on societal and payers' perspectives.
Examination of the reports suggested two different types of model being implemented: Markov model with health states stratified by number of headache days per 28 days as mentioned above [31] or hybrid model with decision tree for 12-week assessment period, classifying participants as responders and non-responders, and Markov model for post-assessment with 12-week cycle lengths [25][26][27][28][29][30]. There were two studies which used a lifetime horizon (25 years) [29, 30] and the rest of them used a time horizon ranging from two to 10 years [25][26][27][28]31]. Further details about the modelling approach, perspective and time horizon used in the models are presented in Table 2.

Resource utilisation and cost
In most of the studies published in the journal articles, the cost included the cost of pharmacotherapy and healthcare resource utilisation. Direct costs included the cost of the medicine and the administration costs, the costs of acute drugs used under usual care, and the costs of hospitalisation, physician, neurology appointment, specialist nurse and/or emergency department visits. Indirect costs for the societal perspective analyses included wages lost on workdays. In some studies (n = 4), the resource use data were obtained from the International Burden of Migraine Studies (IBMS) [16-19, 22, 24] and for other studies, they were either obtained from other published studies or local databases. The NHS reference costs were used as the source of cost inputs in the UK studies [16,19], whereas other studies relied on other specific trials or publicly available sources. All studies included in the reports [25][26][27][28][29][30][31] also included similar resource usage data and unit cost data. The summary of the resource utilisation and the associated cost is illustrated in Table 2.
Price year/currency, the discount rate used and willingness-to-pay (WTP threshold) All studies published in the journal articles reported the currency and price year. The UK studies [16,19] used a 3.5% discount rate for costs and benefits, all other European studies [17,18,21,22], except one [24] and the American studies [20,23] applied a discount rate of 3% for both costs and outcomes. The studies from the UK [16,19]  As in the journal articles, the studies for the reports also reported the currency and price year. The studies from UK used a 3.5% discount rate for costs and benefits [28][29][30][31], the Canadian [28-31] and American studies used a 3% discount rate. Further details on price year/ currency, the discount rate used and the WTP thresholds are illustrated in Table 3.

Utilities and outcomes
The 5-level EQ-5D (EQ-5D-5L) was the main outcome measure used in the economic models. Except for Mahon et al. (2020) [21] study, which used the 3-level EQ-5D (EQ-5D-3L) measure. In four cases [16,17,20,21], the EQ-5D scores were mapped from the Migraine Specific Questionnaire (MSQ). Whereas Sussman et al. (2018) used EQ-5D-5L scores from Erenumab pivotal and open labelled trials (OLE) and Botox pivotal trials [23]. In the case of Hollier-Hann, et al. (2020) [19], utility values were directly obtained from the EQ-5D-5L data collected in the REPOSE study. The EQ-5D-5L was administered at baseline and each follow-up visit (at intervals of approx. 12 weeks) in participants receiving Botox. EQ-5D scores were categorised according to the number of headache days as per the health states in the model and utilities were calculated using the UK value set. For each health state in the Markov model, the mean migraine days (MMD)/28 days specific utilities values were assigned. All            the studies in the reports [25][26][27][28][29][30][31] also used EQ-5D-5L as the main outcome measure. Other outcomes reported by the studies included headache day/year, cost per headache day avoided, cost-saving associated with the use of medicine, headache-related disability, and lost work productivity (Table 3).

A narrative synthesis of cost-effectiveness evidence
In all journal studies which used Botox as the treatment, this was associated with a favourable incremental costeffectiveness ratio (ICER). The use of Botox was costeffective compared to placebo, with an ICER ranging between £15,028 (€17,720) and £16,598 (€19,572) [16,18,19,22]. For example, in the study by Batty et al. [16], an increase in costs of £1367 and an increase in QALYs of 0.1 compared to placebo, resulted in an ICER of £15,028. Treatment with Botox reduced headache days by an estimated 38 days per year at the cost of £18 per headache day avoided. Although the figures for ICERs may be different, in all countries Botox was judged to be cost-effective in their widely accepted respective WTP thresholds. Erenumab, was also found to be cost-effective in participants for whom previous preventive treatments did not work. Two studies also compared the cost-effectiveness of Erenumab against the placebo and found that Erenumab was dominant. For example, Sussman et al. (2021) [23] reported that with an annual drug price of Erenumab at $6900, from a societal perspective treatment with Erenumab is dominant (where it is cheaper and more effective) compared with no preventive treatment among chronic migraine participants. When excluding indirect costs (i.e., payer perspective), the ICERs are costeffective among chronic migraine participants ($23,079 and $65,720 versus no preventive treatment and Botox, respectively [23]. When Erenumab was used as the treatment compared to Botox, the ICERs ranged between £59,712 ($81,080) [20] and £182,128 (€218,870) [17], with the ICERs above the most common WTP thresholds. From the reports, all CGRP inhibitors like Erenumab, Galcanezumab and Fremanezumab were found to be cost-effective in the chronic migraine population for whom the previous three treatments did not work under the widely accepted WTP thresholds [26][27][28][29][30] and have been recommended for such group of participants. More information about the cost-effectiveness of the treatments is provided in Table 3.

Sensitivity analyses
All of the studies were robustly analysed by using deterministic and/or probabilistic sensitivity analyses (PSAs). In most cases, the results were sensitive to changes in monthly migraine days, health utilities, and treatment costs but were cost-effective overall. For example, Hollier-Hann et al. (2020) [19] showed that the administration of Botox by a specialist nurse rather than a neurology consultant reduced the ICER from £16,306 to £13,832 per QALY gained and removal of the positive stopping rule recommended in current NICE guidance increased the ICER to £20,768 per QALY for Botox vs. placebo. Combining these two scenarios produced an ICER of £17,686 per QALY gained. To explore parameter uncertainty, Hollier-Hann et al. (2020) [19] a PSA with 5000 simulations on all model inputs except for drug costs was conducted, generating an ICER of £16,738 which was relatively close to the deterministic ICER of £16,306. Botox had a 71.9% and 94.2% chance of being cost-effective at a threshold of £20,000 and £30,000 per QALY gained respectively. The sensitivity analyses performed in each of the reports were more comprehensive than the journal articles. Further information about the sensitivity analyses is presented in Table 3.
All of the reports were considered to be context-specific and none of them declared any conflicts of interest, although they were funded by the pharmaceutical industries except one report [31].
The journal articles and reports also mentioned if there were any limitations with their studies, further details are shown in Table 4.

Quality appraisal of economic evaluations
The summary of the quality assessment results is presented Table 5. The quality of both the trial-based and model-based economic evaluations was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 checklist [14]. None of the included studies fulfilled all of the quality criteria. The majority of studies fulfilled a large number of quality criteria. The criteria that were the least well-addressed were the items on heterogeneity and generalisability. The quality of the model-based economic evaluations was further assessed using the Philips checklist [15]. Again, the majority of the studies fulfilled a large number of the quality criteria according to the Phillips checklist. The criteria that were least well addressed were whether the data has been assessed appropriately, the principles of uncertainty, heterogeneity, assumption about the   continuity of treatment and its effect, including sensitivity analysis around the assumption of different alternatives of treatment effect.

Discussion
Evidence on the cost-effectiveness of pharmacotherapies for the treatment of chronic migraine was systematically assessed in this review and we identified nine studies that were published in peer-reviewed journals and seven reports [16][17][18][19][20][21][22][23][24]. These studies evaluated four different medicines (Botox, Erenumab, Fremanezumab and Galcanezumab) and were generally classed as high quality when appraised by the CHEERS reporting tool. There has only been one recent review which was published in 2020 assessing the cost-effectiveness of the treatment for migraine including chronic and episodic migraines, however, this was limited to articles published from the UK and the Ireland [12]. Our review provides worldwide evidence and is more comprehensive than this published review. The 2020 review included eight studies and consisted of expert consultations that provided six recommendations on the ideal model structure for migraine that is clinically and economically meaningful. A decision-tree plus Markov structure was then developed for migraine therapies and was recommended for use in future studies. In our review, all the economic evaluations were model-based, and the earlier economic evaluations used Markov models with health states based on the number of headache frequency per 28 days, and the latter economic evaluations used a hybrid model comprising decision-tree plus Markov model approach, including two health states of on treatment and discontinuation once patients were classified as responders or non-responders.
Although the time horizons used by the earlier models ranged from 1 to 10 years, the more recent models used a lifetime horizon. There must be some agreement on this to use in the base-case model to help design future economic evaluations. Additionally, when a societal perspective was adopted, the costs attributed to presentism and absenteeism were far higher than the direct costs. In the earlier Markov models, there was stop/discontinue rules, and these rules were attributed to the fact that medicines can be discontinued in two situations, i.e., in case of when medicines worked or when they do not work (e.g., adverse drug reactions). Any future economic evaluations of chronic migraine treatments should consider such discontinuing rules in the model. The burden that participants experience each day of migraine is meaningful. In a large retrospective, European cross-sectional study, an increase of one headachefree day (HFD) was associated with an average decrease in absenteeism of 3.9% and presenteeism of 2.1% [32]. Resource utilisation was also reduced, with an increase of one HFD being associated with expected decreases in healthcare provider and neurologist visits of 1.0% and 4.7%, respectively. The benefits of each additional HFD corresponded to average increases of 0.003 and 0.008 points for the SF-6D utility score and EQ-5D index score, respectively (p < 0.001 for all) [32]. The burden of migraine is worse for people who need to change preventive therapy. For these patients, 87% reported that migraine had a negative impact on professional, private, or social domains of life [33]. New therapies for chronic migraines, particularly those for treatment-refractory patients, can bring meaningful improvement for participants, and economic evaluations can be useful tools for assessing their value. If comparative data are available, the economic evaluation should include the ability to compare the treatment of interest with other preventive treatments. Compared to other disease areas, the number of economic evaluations in chronic migraine was limited. Many of these evaluations utilised a similar model structure, but each approach has unique strengths and limitations.
The main strength of this review is that it included the latest treatments for chronic migraine such as calcitonin gene-related peptides (CGRP) namely Erenumab, Fremanezumab and Galcanezumab as these have recently been approved for the treatment of chronic migraine. In spite of the worry about cost, these newer and better-tolerated CRGP antagonists treatments are cost-effective despite them being much more expensive than oral preventatives. Another strength of this review is the comprehensiveness of the search strategy used. The search was performed in a broad range of electronic databases of published studies. Furthermore, there were no country and language restrictions. The review also had some limitations. We only included full economic evaluations. Therefore, some important data contained within partial economic evaluations might have been missed. Another limitation of the study includes the unclear definition of comparators, such as best supportive care, placebo and preventative treatment within the included studies. But there was a general agreement within the studies that the people in comparator groups were allowed to take their usual acute headache medicines such as triptans. In addition to these limitations, the shortcomings of the included studies and underlying evidence base as mentioned in the individual studies were further limitations. Potential publication bias may also be a problem. It is possible that any study that did not find positive evidence of the use of other chronic migraine treatments did not conduct an economic evaluation or, if they did, this may not have been published.

Conclusion
Evidence to support the cost-effectiveness of pharmacological treatments of chronic migraine in the adult population using Botox and CGRP inhibitors such as Erenumab, Fremanezumab and Galcanezumab, were identified. Based on the findings from the review, Botox and CGRPs, both were cost-effective compared to placebo; although the CGRPs had more incremental economic benefits compared to Botox, the ICERs were above the most common willingness-to-pay thresholds. CGRPs might provide an acceptable cost-effective prophylactic treatment for chronic migraine including for participants for whom the other treatments including Botox have been unsuccessful. Further research is needed to better characterise the data to adequately structure and parameterise an economic model to support decision-making for chronic migraine therapies.